Most cardiac surgical procedures require induction and management of myocardial ischemia and reperfusion. Preconditioning by a brief period of unprotected ischemia and reperfusion confers myocardial protection subsequent to a more prolonged insult. The central hypothesis of this application is that understanding the changes in sarcolemmal membrane currents which underlie the ability of the myocyte to maintain excitability consequent to preconditioning may provide an avenue for new approaches to myocardial protection that would improve myocyte function as well as survival. Our novel models use guinea pig myocytes isolated preischemically, prior to metabolic inhibition by NaCN, and rabbit myocytes first exposed to global ischemia, and then isolated during reperfusion. Studies of intracellular calcium and pH, and sarcolemmal current-voltage relations demonstrate an increase in an outward potassium current that appears either during prolonged ischemia, or during reperfusion. This current is not blocked by glybenclamide, indicating an identity other than i(kATP) Ischemic preconditioning shortens the time to appearance of the current during ischemia, and prevents its expression during reperfusion. Using these biological markers, our specific aims are to study, 1.) whether preconditioning triggers intracellular calcium, pH, or potassium conductance changes evident during preischemia, 2.) whether depolarizing (K+ or K+/Mg ++) and/or hyperpolarizing (pinacidil or ACh) cardioplegic ischemia imparts protection by sarcolemmal conductance and intracellular ionic changes similar to preconditioning evident during reperfusion, and 3.) whether maintenance of a specific membrane potential during ischemia limits deleterious biophysical changes, and whether i(kl) or other inward rectifiers may act as mediators of the observed K+ current changes. This translational research effort supports our long-term aim to understand the biophysical mechanisms and triggers that will direct the development of specific methods to enhance the clinical conduct and outcome of cardiac ischemia for patients who must undergo surgical repair.